Subjects who smoke marijuana have reduced intraocular pressure (Helper et al, J. Am. Med. Assoc., 217:1392 (1971)). The primary psychoactive ingredient in marijuana is known to be delta-9-tetrahydrocannabinol ("THC"). Human experiments involving intravenous administration of pure THC have confirmed the intraocular pressure reduction phenomenon seen with subjects who smoke marijuana (Cooler et al, South. Med. J., 70:954 (1977)). As a result, cannabinoids have been investigated as anti-glaucoma agents.
However, use of systemic cannabinoids, such as THC, as anti-glaucoma agents is disadvantageous since they can cause significant adverse psychological and physiological side-effects. In addition, cannabinoids are lipophilic compounds that are very insoluble in water, thus hindering their application as topical ophthalmic pharmaceutical products.
Anandamides are structurally different from cannabinoids, such as THC. The first anandamide discovered (Devane et al, Science, 258:1946 (1992)) is represented by the following formula, and is known as arachidonyl ethanolamide: ##STR1## Two other endogenous anandamides were subsequently discovered (Hanus et al, J. Med. Chem., 36:3032 (1993)). Several synthetic analogues have also been made (Felder et al, Proc. Natl. Acad. Sci. USA, 90:7656 (1993); Abadji et al, J. Med. Chem., 37: 1889 (1994); Pinto et al, Pharm. Exp. Therap., 46:516 (1994); and Adams et al, Life Sciences, 56:2041 (1995)).
Arachidonyl ethanolamide is an endogenous porcine ligand reported to bind to the cannabinoid receptor in the brain (Devane et al, supra). Like THC, anandamides are useful in reducing intraocular pressure (PCT Patent Publication Wo 94/12466). However, it has been discovered in the present invention that many anandamides, when used as a hypotensive agent, have a disadvantage in that a hypertensive effect is induced during the initial phase of action.
Aqueous eyedrops are the most commonly used dosage form for ophthalmic drug delivery. This is because eyedrops are easy to use, relatively inexpensive and do not impair vision. However, the aqueous solubility of anandamides is very poor. Thus, ophthalmic delivery of anandamides in aqueous eyedrops is difficult.
Anandamides are soluble in oil solutions (e.g., castor oil, sesame oil, mineral oil, etc.) and organic solvents (e.g., ethanol, chloroform, etc.). However, these solvents cause harmful side-effects when administered to the eyes. Thus, they are generally not used for ophthalmic drug delivery.
Cyclodextrins ("CDs") are a group of homologous cyclic oligosaccharides consisting of six, seven or eight glucopyranose units, and are respectively called .alpha.-, .beta.- or .gamma.-cyclodextrin. It is generally known that CDs can form inclusion complexes with various hydrophobic organic or inorganic compounds, and as a result, increase the solubility or stability of these compounds (Bekers et al, Drug Dev. Ind. Pharm., 17:1503-1549 (1991); and Duchene et al, Drug Dev. Ind. Pharm., 16:2487-2499 (1990)). CDs have also been used to increase the dissolution rate, as well as the bioavailability of various drugs, and to decrease the toxicity of topically applied drugs (Bekers et al, Drug Dev. Ind. Pharm., 17:1503-1549 (1991)).
CDs can be regarded as cone-shaped molecules, where the polar hydroxyl groups of the glucose unit are oriented towards the outside of the structure (Bekers et al, Drug Dev. Ind. Pharm., 17:1503-1549 (1991)). Therefore, the outside of CDs is hydrophilic, whereas the inside of the cavity is hydrophobic in character. The minimum requirement for inclusion complex formation is that the guest molecule must fit, entirely or at least partially, into the CD cavity (Bekers et al, Drug Dev. Ind. Pharm., 17:1503-1549 (1991)).
However, little attention had been paid to the suitability of CDs for use with drugs having ophthalmic activity or for use in ophthalmic compositions. Co-administered CD has increased the ocular absorption of dexamethasone (Loftsson et al, Int. J. Pharm., 104:181-184 (1994), dexamethasone acetate (Usayapant et al, Pharm. Res., 8:1495-1499 (1991) and pilocarpine (Freedman et al, Curr. Eve Res., 12:641-647 (1993), and the intraocular pressure lowering effect of carbonic anhydrase inhibitors (Loftsson et al, Eur. J. Pharm. Sci., 1:175-180 (1994) (see also EP 326196B1, EP 400637A3, EP 435682A2 and EP 472327A1).